This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Purpose: To assess the effect of PD-1 blockade on T cell dynamics and function, immune activation and viral replication in SIV-infected rhesus macaques in stable plateau phase. Hypothesis: Blocking the cellular activation inhibitory pathways PD-1/PD-L1 in vivo will enhance T cell activation, proliferation, and function resulting in better control of viremia and improved overall T cell function and homeostasis without significant triggering of unbalanced immune activation. Rationale and Significance: PD-1 is upregulated on HIV-specific T cells, and expression levels are significantly correlated with both viral load and the reduced capacity of cytokine production and proliferation of HIV-specific CD8 T cells. Blocking the PD-1/PD-L1 pathway in vitro enhanced the capacity of HIV-specific CD8 T cells to proliferate and led to an increased cytokine and cytotoxic molecules production in response to cognate Ags. We have also recently reported that PD-1 level of expression correlates with the level of functionality of SIV-specific T cells. Moreover, our preliminary results indicated that PD-1 level of expression was also upregulated on memory compared to na[unreadable]ve B cells following viral infections. In addition, human anti-PD-L1 antibody (Medarex, MDX-1105), shown to enhance T cells activation and proliferation, was recently approved for Phase 1 clinical trial involving patients with advanced or recurrent solid tumors. Based on these findings, we hypothesized that in vivo blocking of PD-1/PD-L1 interaction would significantly enhance the activity, function, and proliferation of SIV-specific T cells. Of note, treating mice with anti-PD-1 was proven to be tolerated (safe) and did not induce toxic immune activations. This approach is expected to boost immunity against SIV/HIV chronic infection and would, hence, have a profound impact on treatment/vaccination against these viruses. This work was completed in the last year and revealed that administration of anti-PD-1 transiently increased the regeneration and function of CD4 memory T cells in SIV-infected monkeys, as well as normalized the gene expression pattern of both CD4+ and CD8+ memory T cells. These data have been used to seek long-term NIH funding to further explore the mechanisms and biologic implication of these findings.